4-carbalkoxy-3-keto-2-substituted tetrahydrothiophene oximes



Patented Apr. 4, 1950 UNITED STATE 4-CARBALKOXY-3 KETO 2- SUBSTITUTED TETRAHYDROTH IQPHENE OXIMES Lee C. Cheney, Syracuse, N. Y., and John Robert Piening, Detroit, Mich, assignors to Parke; Davis & Company, Detroit, Mich, a. corporation of Michigan No. Drawing. Original application December 23, 1944, Serial No. 569,639. Divided'and this application April 1, 1946, s fillal Nth $58,374-

wherein. R. is a lower saturated alkyl group,.n is 1 to 8 and the alkyl chain (CnH2n-) maybe straighter branched and R is a. radical of the class -COOH, COOM, COORQ aryloxm,

aralkoxy and alkoxy, the group M representing a ,salt-forming-basic group. or metal such as sodium or other alkali metal. alkaline earth metals, mag

nesium, ammonium and substituted ammonium, such as monoalkyl and dialkylammonium.

These new compounds are useful as intermediates in the synthesis of compounds of medicinal interest, particularly of compounds possessing biotin or possibly anti-biotin activity.

4-carboalkoxy-3keto-2-alkyl tetrahydrothiophenes having one of the above mentioned groups, R, substituted on a carbon atom of the 2-alkyl group, CnH2n-, are prepared by methods disclosed in our application, Serial No. 551,619, filed August 28, 1944. Said method consists in an internal condensation in the presence of an alkali metal alkoxide of a fi-carboalkoxyalkyl-a-carboalkoxyalkyl sulfide, wherein the alkyl carrying the e-carboalkoxy group also carries the substituent R. We have now found that these compounds are readily converted at the 3-keto group into their corresponding oximes by the action of a hydroxylamine salt in the presence of an acidbinding agent.

The process of the instant divisional application may be represented as follows:

GOOR soon i r it -'o raNorLacia H -o P I I mo CHC,.H2,.R acid-bind- H2O CH-C,.HMR

8 ing agent suitable acid-binding agents include the bicarbonates, carbonates, oxides and hydroxides of 4 Claims. (Cl. 260-329) i the alkali and, alkaline;

salts of lower carboxylic acids, alkali metal alkoxe,

earth metals, the alkali ides, ammonium hydroxide, and organic bases such as alkyl amines, pyridine, piperidine, etc.

i The following examples illustrate methods of carrying out the invention, but its scope is not.

to be limited by the reactants and conditions cited therein. as; will be apparent to those skilled in the art:

Example. 1'

Ethyl 4 carbethomy-3-iceto-2tetmhydrothiophene'ualerate ozvime.-A solution of 30. g. (0.1 mole) of ethyl 4-carbethoxy-3keto-Z-tetrahy- "1 drothiophenevalerate in 300 ml. of absolute alcohol is refluxed on the steam bath: with 34.8 g. (0.5 mole) of hydroxylamine hydrochloride and 59 g. (0.3 mole) of anhydrous barium carbonate for seven hours. The mixture is filtered and inorganic salt on the filter is washed with hot absolute alcohol. The alcohol is removed under reduced pressure and the residue is taken: up in ether, washed with water and dried over sodium. sulfate. Salt and. then ether are removed and the residue dried over P205 in a vacuum desic cator. The oxime: is an. oil and. weighs 29.87 9...; yield 94%.

- cop ous;

non He? mt cn- 05940 OlOQgH Example 2 4-carbethomy 3- lceto-Z-y-phenOxypmp ZtetTahydrothiophene O:cime.A mixture of 30.8 g. (0.1 mole) of 4carbethoxy-3-keto-2-v-phenoxypropyltetrahydrothiophene, 30.8 g. (0.443 mole) of hydroxylamine I-ICl, 46.2 g. (0.234 mole) of anhydrous BaCOs and 300 ml. of abso ute alcohol is refluxed on the steam bath for 22 hours and then allowed to stand for two days. The solution is warmed and then filtered using suction. The inorganic residue is washed with 200 ml. of hot absolute alcohol. The filtrate is distilled at reduced pressure. The residue is dissolved in 800 ml. of ether and washed with 500 ml. of water in 3 portions. The ether extract is then dried over NaaSOr for six hours. Ether is removed and the residue dried overnight in a vacuum desiccator over P205. In the morning the oxime has partially crystallized and is considered good enough for further synthesis. The yield is 30.35 g. or 94%. A portion of the thick semi-solid mass is treated with a small portion of 95% alcohol and the crystals which fail to dissolve are crystallized from 80 alcohol to obtain colorless crystals, M. P. 101 C.

AnaZ.Calcd. for C16H21O4NS1 C, 59.42; H, 6.54; N, 4.33. Found: C, 59.26; H, 6.33; N, 4.56.

Its formula is,

Example 3 4-carbethoxy-3-lceto 2 'y benzyloirypropyltetrahydrothz'ophene oxime.A mixture of 189 g. (0.586 mole) of 4-carbethoxy-3-keto-2-a-benzyloxypropyltetrahydrothiophene, 189 g. (2.72 moles) of hydroxylamine hydrochloride, 296 g. (1.50 moles) of anhydrous BaCOs and 1500 ml. of absolute alcohol is refluxed on the steam bath for 22 hours. The inorganic salts are removed and washed with alcohol. The filtrate is distilled under reduced pressure to remove alcohol. The residue is taken up in 2 liters of ether and is washed with water and saturated NaCl solution, then dried over Nazsoi for 18 hours. Ether is removed after filtering ofi Na2SO4. The oil is dried in a vacuum desiccator to constant weight. Yield 175 g.; 89%.

AnaZ.-Ca1cd. for C17H2204S: C, 63.32; H, 6.87. Found: C, 63.41; H, 6.61.

Its formula is,

Although various reagents and reaction media can be used in the process of this invention, We prefer to use those compounds, dilutions and other conditions which do not result in any substantial hydrolysis of the ester group COOR' at position 4 of the heterocyclic ring.

What we claim as our invention is:

1. An oxime of the formula,

COOR

where R is a lower alkyl radical, n is an integer from 1 to 8 inclusive, R is a member of the class consisting of COOH, COOM, COOR, aryloxy, aralkoxy and alkoxy, M being a salt-forming basic group.

2. Ethyl 4-carbethoxy- 3- keto 2 tetrahydrothiophenevalerate oxime of formula,

3. 4-carbethoxy-3-keto-2 'y phenoxypropyltetrahydrothiophene oxime of formula,

4. 4-carbethoxy-3 keto-2- \-benzyloxypropyltetrahydrothiophene oxime.

LEE C. CHENEY. JOHN ROBERT PIENING.

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Name Date Schnider Mar. 11, 1947 OTHER REFERENCES Number 

1. AN OXIME OF THE FORMULA, 